Grant: Operating Grant

Human cell nuclei contain several structures referred to as PML bodies because PML (promyelocytic leukemia) proteins form the basis of these structures and alterations to the PML proteins result in loss of these nuclear bodies. PML nuclear bodies control many important cellular processes including the repair of damaged DNA, cell proliferation and programmed cell death. Due to these important functions, the loss of PML bodies appears to be an important factor in the development of several types of cancer but the cellular proteins that control the loss of PML bodies are only partly understood. In addition, PML bodies are part of the cell's defense mechanism to suppress viral infection and viruses in turn have developed mechanisms to disrupt PML bodies thereby facilitating their own replication. We have recently identified a human protein (USP7) that functions to regulate the levels of PML bodies and PML proteins in the cell and that is usurped by some viral proteins for this purpose. In addition, a screen of 234 proteins from 3 herpesviruses identified 22 viral proteins that modulate or disrupt PML bodies. We propose to determine the mechanisms by which USP7 and these viral proteins function to alter and disrupt PML bodies and their functional consequences. This information will greatly increase our understanding of how the formation and loss of PML bodies is regulated and how changes in PML bodies affect cellular processes that control cell transformation and determine whether the cell lives or dies.